The nociceptin receptor (NOP, previously known as the opioid receptor-like receptor ORL1) is the fourth member of the opioid receptor family. The NOP receptor and its endogenous ligand nociceptin or orphanin FQ (N/OFQ) have been shown to play a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the natural peptide N/OFQ or the only studied synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various rodent models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. N/OFQ and Ro 64-6198 have also been shown to have anxiolytic activity in rodent models of anxiety and anti-CRF activity in rodent models of stress-induced drug-seeking behavior. This pharmacological profile of the anti-rewarding and anti-stress effects of the NOP-N/OFQ system suggest that the NOP receptor is a viable pharmacologic target for treatment of drug abuse and relapse, and that small-molecule NOP agonists may have potential as drug abuse pharmacotherapy. However, the development of therapeutically viable, small-molecule NOP ligands has not yet progressed to the clinic and NOP agonists have not yet been evaluated in translational primate models of drug self-administration and relapse, possibly, because known NOP agonists are either not sufficiently selective or have poor bioavailability. Clearly, next generation, drug-like compounds are needed to produce clinically useful medications. The overall objective of our currently funded grant is to discover novel, selective and drug-like NOP agonists and antagonists and investigate their activity in rodent models of opiate and cocaine reward and as non-addicting analgesics in models of pain. We have discovered several selective NOP ligands, and recently demonstrated that our NOP agonist SR16835, attenuates morphine place preference in mice and reduces deprivation-induced increase in alcohol drinking in Wistar rats (a model of relapse). In this Competing Revision, in response to Notice #NOT-OD-09-058, entitled: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications', we propose to study our NOP ligands in 'nonhuman primate'models of cocaine reward and relapse. These studies will provide critical information that will accelerate the translation of NOP agonists for drug abuse treatment. To discover useful NOP ligands, an understanding of the receptor molecular recognition features that lead to NOP selectivity versus other opioid receptors is critical, to be able to modulate drug-like characteristics while maintaining selectivity and affinity. In this Revision, we also propose to increase the scope of our ligand discovery by integrating structure-based drug design into our drug discovery efforts. The Specific aims of this Competing Revision are (1) develop predictive 3D-QSAR CoMFA models and a NOP receptor homology model to support the site-directed mutagenesis studies and NOP ligand design and (2) To investigate selected NOP agonists in primate models of cocaine self-administration and relapse. PUBLIC HEALTH RELEVANCE: NOP agonists have been shown to decrease the rewarding effects associated with drugs of abuse and also to have anti-stress related activity, suggesting that the NOP agonists have potential as drug abuse pharmacotherapy and for prevention of relapse. The work proposed in this Competing Revision in response to the ARRA notice NOT-OD-09-058, will specifically accelerate the translation of our selective NOP agonists by studying their efficacy in nonhuman primate models of drug self-administration and relapse. This project also proposes to incorporate current new technology, structure-based drug design, into our existing discovery efforts, to accelerate the discovery of drug-like, potent and novel NOP agonists. The proposed studies will significantly accelerate the translation of the project toward the development of therapeutically viable NOP agonists as drug abuse treatment medications.